At present, single-dose oral preparations are primarily packed in aluminum-plastic blister packages in the pharmaceutical area. Such packages have many advantages. First, it provides single-dose pharmaceutical packages for patients that are quite convenient and economical and avoids over dosage or insufficient dosage by patients. Second, blister package production is fast with low cost, takes up less storage space and is convenient to transport. Lastly, it is safe because the surface of the aluminum foil contains explanatory notes, which can help avoid mistakes during drug distribution when multiple drugs are distributed. Therefore, oral preparations with blister packages will dominate the market for a period of time in the future. However, the polymer materials used in blister packages, by their own properties, cannot prevent light and moisture from permeating the packages or contacting the pharmaceuticals contained therein, and thus affect the quality of the pharmaceuticals. To solve this problem, double aluminum layer packages, wherein the blister packages contain complex aluminum materials having polymer materials attached to the top and bottom of the aluminum foil, were used. The strong blocking property of the aluminum foil prevents the pharmaceuticals from damages brought about by outside factors such as light, moisture, bacteria, etc. and therefore extends the storage life of the products. This kind of package is important to pharmaceuticals that are vulnerable to effects from the outside environment, especially to the oral disintegrating preparations. If the oral disintegrating preparations are exposed to the moisture in the air, they may shrink substantially, which will prolong the disintegrating time and result in the products' failure to meet the quality requirements.
In addition, an oral disintegrating preparation can rapidly disintegrate in the mouth when it contacts the saliva without the need of water to wash it down, which is convenient to patients who have swallowing problems or cannot access water. More and more patients appreciate its unique advantages. Meanwhile, as the research has deepened, it has been discovered that besides its easy administration, this kind of preparation can be absorbed through mouth, throat and esophagus mucous membranes and thus takes effect quickly. Therefore, it can be used to develop pharmaceuticals for treating acute diseases such as pain diseases, insomnia, vomit, epilepsy, allergic and heart diseases, etc. The preparation can reduce the first pass effect of the liver, enhance medicine utility, reduce toxicity, and so on. It also has a great market prospect and has become the hotspot for research and development in the new formulation area and thus has attracted great attention.
Methods of manufacturing oral disintegrating preparations mainly include the direct compression process and the freeze-drying method. Tablets manufactured using the direct compression process have the biggest carrying capacity, the lowest cost and the widest application range. But the molding of the tablets and the time required for disintegration are contradictory to each other. In other words, the more pressure the compression has, the better the tablets will be molded, but this will prolong the disintegrating time. On the other hand, in order to ensure faster disintegrating speed, the tablets will be loose and may be worn down or even broken in the process of packing, storage and transportation.
In order to solve the problems concerning the direct compression process, oral disintegrating tablets manufactured with the freeze-drying method appeared in the market, for example, the Zydis technology. But using this technology leads to other problems. Because pharmaceuticals together with complex package materials are molded and rapidly frozen in ultra low temperature during the manufacturing process, the substrate materials of the package materials warp after the freeze-drying and affect the subsequent process. For example, it will have adverse effects on the sealing process and decrease the product quality. To solve these problems, CN 93121709.1 published a method of manufacturing oral disintegrating preparations using complex aluminum as substrate materials in the freeze-drying method by which the thermal expansion coefficients of the first and second outer layers of the substrate materials of the package must be the same. In this published document, the principle of requiring the same thermal expansion coefficients of the substrate materials is that, when the substrate materials are subject to the temperature changes in the process of freeze-drying, the first outer layer and the second outer layer must respond symmetrically to the temperature changes in order to prevent the substrate materials from warping after freeze-drying. The first and the second outer layers of the substrate materials must have the same thermal expansion coefficients so as to have symmetrical reaction to the temperature changes.
But the inventors of this invention discovered in their studies that during the aforesaid manufacturing process, the reason that the substrate materials warp before sealing the pharmaceuticals with lidding materials is that they are affected by the joint effects of two processes, namely, the aluminum depression molding process of the substrate materials and the freeze-drying process after filling in the pharmaceuticals. Meanwhile, the inventors of this invention further discovered through numerous experimentations that although the warp of the substrate materials is affected by the aforesaid two processes, the molding process exercises the most influence. Although the freeze-drying process also has influence on the warp of the substrate materials, its effect is negligible when compared with that of the molding process. This indicates that as long as the substrate materials do not warp after the molding process, it will satisfy the technical requirements even if it warps a little in the process of freeze-drying. After a long time of research and experimentation, the inventors of this invention finally discovered the technical solution to this question, and thus have accomplished this invention.